The overall goal of Project 1 is to determine, through a series of non-small cell lung cancer (NSCLC) clinical trials, whether proton therapy in its current state of the art or with the advances achieved through physics research proposed in Projects 3 and 4 would lead to superior outcome compared to photon therapy. Despite the apparent physical advantages of proton dose distributions, the answer to this question is not obvious because of the challenges of intra-fractional motion, inter-fractional anatomic changes (e.g., due to tumor shrinkage and weight loss), internal inhomogeneities, low density of lung tissue and other sources of physical and biological uncertainties. These factors affect the range of protons and cause the dose distribution seen on a treatment plan to be different from the dose distribution actually received by the patient. Initial trials will be conducted with the current state of the art of proton therapy. Physics investigations proposed in Projects 3 and 4 will lead to improved accuracy and quality of proton dose distributions. Additional clinical trials conducted with the advanced state of the art of proton therapy will allow the evaluation of the true potential of protons vs. photons. The aims of this project are: 1) Stage II-IIIB Randomized Trial: a reduction in the rate of pneumonitis with equivalent tumor control may be realized using protons compared to photons in patients with stage II-IIIB NSCLC receiving concurrent chemotherapy and will be tested in a Bayesian adaptive randomized trial, 2) Stage II-IIIB Phase l/ll Dose Escalation Trial: local control can be improved in patients with stage II-IIIB as a result of higher fraction sizes and total radiation doses to gross tumor volume delivered by simultaneous integrated proton boosts without increasing toxicity when concurrent chemotherapy is used. 3) Stage l/ll Phase l/ll Trial: proton therapy with standard fractionation and higher BED may have a higher maximal tolerated dose (MTD) compared with conventional photon therapy, 4) Stage //// Randomized Trial: proton therapy (from Aim 3) compared to highest dose regimen safely achieved with photon therapy can lead to improved local control in centrally located stage IA or stage IB and selective stage II (T3NOMO) NSCLC, 5) Hypofractionated (-10 CGE per fraction or higher) Stereotactic Body Proton Therapy (SBPT) of centrally located Stage I. The significance is that the results of our studies will allow us to determine which NSCLC patients are most likely to benefit from proton therapy, and to set the stage for cooperative trials.